Long-term cigarette smoking is a leading cause of pulmonary emphysema, in which loss of elasticity in lung tissue leads to alveolar enlargement and coalescence, and impaired gas exchange. Extracellular proteases, which help control that elasticity, have been implicated in the development of emphysema, but how these enzymes are regulated has been unclear. In the March 13 Nature, Dean Sheppard and colleagues at the University of California, San Francisco, US, identify a regulatory pathway whose downstream metalloproteinase target can induce emphysema, and whose upstream regulators include the widespread growth factor, transforming growth factor-β (TGF-β) (Nature 422:169-173, March 13, 2003).

Sheppard et al. analyzed pulmonary gene expression in knockout mice lacking the integrin αvβ6 gene, an epithelial cell-surface protein which binds and activates latent TGF-β. Expression of the metalloproteinase Mmp12 — which degrades the connective tissue protein elastase — increased 18-fold, and the mice developed progressive emphysema. This...

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